Comparative Outcomes of Radical Cystectomy in Muscle-Invasive Bladder Cancer: A Systematic Review and Meta-Analysis

Muscle-invasive bladder cancer poses a significant clinical challenge that necessitates effective therapeutic interventions. Radical cystectomy is a primary treatment option, but a comprehensive understanding of its outcomes is crucial for informed clinical decision-making. This systematic review and meta-analysis aimed to investigate and summarize the outcomes associated with radical cystectomy as a primary treatment for muscle-invasive bladder cancer with a focus on survival rates, complications, and quality of life. A systematic search across databases-PubMed, Google Scholar, and others-covered studies from 2017 onwards. Included were studies reporting survival rates, complications, and quality of life post-radical cystectomy in muscle-invasive bladder cancer patients, including randomized controlled trials, cohort, and observational studies. Multidimensional analysis revealed promising findings regarding the efficacy of radical cystectomy in muscle-invasive bladder cancer. Survival outcomes, including overall survival and disease-specific mortality, have demonstrated significant improvements, particularly in recent randomized controlled trials and cohort studies. Complications associated with the surgical procedure, such as positive surgical margins and lymph node yields, were generally acceptable. Quality of life outcomes post-radical cystectomy exhibited positive trends, although variations were noted in the emotional and social domains. This review underscores radical cystectomy's role in enhancing overall survival and reducing disease-specific mortality in muscle-invasive bladder cancer. Despite reported complications, recent studies support its acceptable risk profile. Detailed examination of various factors contributes to a comprehensive understanding of the procedure. These findings emphasize the importance of individualized treatment approaches in the management of muscle-invasive bladder cancer, considering both oncological efficacy and perioperative outcomes. Radical cystectomy remains fundamental in urological oncology, with ongoing advancements refining its significance.


Introduction And Background
Bladder cancer, a complex and heterogeneous malignancy, is one of the most prevalent cancers worldwide.It is characterized by uncontrolled cell growth within the bladder lining and poses a significant public health concern with varying incidence rates worldwide [1,2].The latest global cancer burden report utilizing GLOBOCAN 2020 data was released by the International Agency for Research on Cancer (IARC) [3].In 2020, they revised the figures for bladder cancer, estimating 573,278 new cases and 212,536 deaths worldwide [3].For the United States, in 2021, the projected numbers were 83,730 new cases and 17,200 deaths from bladder cancer.Notably, a consistent trend of higher incidence and mortality among males persisted across various countries and regions [4].
The burden of bladder cancer extends beyond its high incidence as it imposes considerable economic and healthcare challenges.Its insidious nature often leads to delayed diagnosis, prompting the exploration of diverse therapeutic modalities to address the complexity of its clinical presentation.Available treatments range from intravesical therapies for non-muscle-invasive diseases to radical interventions for muscleinvasive diseases [5].Muscle-invasive bladder cancer (MIBC) is a critical juncture in disease progression that demands decisive and efficacious interventions.Among the therapeutic armamentarium, radical cystectomy has emerged as a cornerstone for managing MIBC, particularly when considering the intricate balance between achieving oncological control and preserving patients' overall quality of life (QoL) [6].This surgical procedure involves the removal of the entire bladder, potentially extending to nearby tissues, and often includes the creation of a urinary diversion.The choice of radical cystectomy is influenced by its potential to provide definitive oncological control while allowing for adaptation to various clinical scenarios [7].
The justification for a comprehensive evaluation of radical cystectomy outcomes in MIBC lies in the evolving landscape of oncological care and the imperative to optimize treatment strategies.Recent years have witnessed advancements in surgical techniques, perioperative management, and a growing emphasis on patient-reported outcomes [5].Therefore, a systematic review and meta-analysis (SRMA) is essential to

Objectives
The objectives of this analysis were to (1) systematically assess and synthesize the latest evidence on survival rates following radical cystectomy as a primary treatment for MIBC; (2) analyze and aggregate data on surgical and medical complications associated with radical cystectomy in MIBC, providing a comprehensive overview of treatment-related morbidity; (3) evaluate the impact of radical cystectomy on patients' QoL by synthesizing findings related to physical, emotional, social, and functional well-being; (4) compare outcomes of radical cystectomy with alternative treatments for MIBC, where data permit, contributing to the understanding of treatment efficacy in the context of available therapeutic options; (5) conduct a thorough assessment of publication bias by analyzing and reporting the potential selective reporting of outcomes in the included studies.

Definitions
MIBC is characterized by the infiltration of cancerous cells into the muscular layer of the bladder wall.This stage of bladder cancer poses a higher risk of progression and requires aggressive treatment approaches [9].Radical cystectomy is a surgical procedure involving the removal of the entire bladder, often including nearby tissues such as lymph nodes and surrounding structures.This is the primary treatment option for MIBC [10].Survival outcomes encompass various measures, including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS), providing insights into the effectiveness of radical cystectomy in extending and preserving patients' lives [11].Complications include adverse events or unwanted outcomes associated with radical cystectomy, including surgical and medical complications [12].QoL outcomes encompass patients' physical, emotional, social, and functional well-being following radical cystectomy.These outcomes provide a holistic understanding of the impact of treatment on individuals [13].

Eligibility Criteria
We set the eligibility criteria for studies following the Population, Intervention, Comparison, Outcome, and Study Design (PICOS) scheme, as recommended by the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA).
The inclusion criteria were as follows: (1)

Information Sources
We searched several digital databases for relevant studies.These included PubMed, Google Scholar, ClinicalTrials.gov,ScienceDirect, MEDLINE, Embase, etc. Independent journals and other sources were also included.The "World Journal of Urology "BJU International," "BMJ," "Elsevier," "Scandinavian Journal of Urology" and others were sources of literature other than databases.

Search Strategy
We found a total of 17 studies (n=956) that were eligible for the inclusion criteria and covered the terms: ("Radical cystectomy" OR "cystectomy" OR "bladder removal") AND ("muscle invasive bladder cancer" OR "MIBC" OR "invasive urothelial carcinoma" OR "locally advanced bladder cancer") AND ("survival" OR "mortality" OR "complications" OR "adverse events" OR "quality of life") AND ("bladder cancer patients" OR "patients with muscle-invasive bladder cancer" OR "urothelial carcinoma patients").
Filters: Abstract, Free full text, Clinical Study, Clinical Trial, Meta-Analysis, Randomized Controlled Trial, Systematic Review, in the last 5 years, Humans, English.Additionally, we inspected the reference lists of the studies selected for systematic review and meta-analysis.

Selection Process
Four researchers searched for literature in peer-reviewed journals and publications in accordance with inclusion criteria.After a thorough selection of the literature, peer-reviewed journals with a strong impact factor were explored to reduce the risk of publication bias.All selected studies were uploaded to the screening software Rayyan.aifor primary and secondary screening of literature [14].Four researchers worked as collaborators to "include" or "exclude" eligible studies based on the inclusion and exclusion criteria.
Seventeen studies (N =182) were included in the final review and analysis.Studies that did not pass the eligibility for screening were put under "exclusion" or "dispute."We created a team of four researchers for study selection to serve as tiebreakers for disputed studies.Reasons for exclusion were proposed before excluding a study from the literature.Studies were excluded because (1) there was a problem with the population, (2) suboptimal study design for analysis, (3) the study measured inappropriate outcomes, or (4) we found a high risk of bias.Occasionally, a combined effect of multiple reasons for exclusion was observed.

Data Items
The total sample size of the selected studies (n=17) was scrutinized after completion of the secondary screening protocol.We used the PRISMA standards to create a PRISMA flow diagram for selected studies from journals and other independent resources (if reports were available) [15].The PRISMA flow diagram is given in Figure 1.Bias in the analysis was minimized by (1) selecting high-quality research and thorough literature review, (2) eliminating the double standard concerning peer review and informed consent applied to clinical research and practice, (3) requiring peer reviewers to acknowledge conflicts of interest, and (5) replacing ordinary review articles with meta-analyses.Systematic and narrative reviews were frequently excluded from the literature to maintain the standards of the study.These guidelines detect and remove bias in the study protocol in accordance with the Chalmers et al. (1990) stages of removing publication bias [16].All the studies chosen for the meta-analysis were found to have a "low" overall risk of bias and assessed by the Critical Appraisal Skills Programme (CASP) tool.

Study Characteristics
The final sample for the systematic analysis included 17 peer-reviewed studies; 15 retrospective cohort studies and 2 prospective cohort studies.Twelve of these studies used randomization, and 11 used a (quasi)-experimental design, 6 of which used Cox regression methods to construct a matched comparison group.One study used latent curve modeling.Sample sizes ranged from as small as N=36 to as large as N=32,300.The follow-up data collection time points ranged from 2 months to 24 months (2 years).The results of the systematic analysis revealed a total of 12/17 (71%) studies advocated that the OS of radical cystectomy was slightly better.On the other hand, 5/17 (29%) studies concluded "no effect" or "negative" association of any effect proving radical cystectomy has overall benefit.The synthesis table for the systematic review is given in Table 1.There is potential to yield comparable oncological outcomes,

CASP Assessment
Table 2 employs the CASP tool to assess various studies on muscle-invasive bladder cancer.

S.
No.

Forest Plot for Overall Survival
A forest plot was generated for nine individual studies using a generalized inverse variance approach to measure the hazard ratio (HR) as the primary outcome.A random-effects model was employed to calculate the hazard ratio (HR) in terms of "log[HR]" and standard error "(SE)."The confidence interval (CI=95%) is plotted on the horizontal axis, with red squares representing the 'point estimation' on the plot.The total sample sizes (n=2316, 112, 340, 3200, 8454, 2306, 218, 1472, and 6325) remained relatively stable in the control groups.The central vertical line on the plot denotes a state of "no effect."The forest plot summarizes the quantitative data for each study and provides an estimated overall quantitative value for all combined effects.The overall combined effect size was calculated, yielding z=2.09, CI=95% (1.01, 1.32).Notably, the individual effect size was found to be significant in five out of the nine studies:  [17,19,23,[27][28][29][30][31].This indicates that the individual effects of five out of nine studies favored the control group, that is, the population undergoing radical cystectomy (RC).The results of this study (HR=1.15,CI [1.01, 1.32] ) favored "Radical Cystectomy," suggesting prolonged overall survival compared to other bladder preservation treatment modalities.This study aligns with the analysis conducted by another meta-analysis by Su et al. ( 2023) [34].Figure 2 shows a forest plot of the meta-analysis.

FIGURE 2: Forest plot for overall survival
Forest Plot for Progression-Free Survival The forest plot for progression-free survival in RC synthesized quantitative data from each study, providing an estimated overall quantitative value for the combined effects.The overall combined effect size was calculated as z=0.69,CI=95% (0.85, 1.41).Notably, the individual effect size was found to be statistically  2022) [17,19,26].This suggests that the individual effects of four out of the six studies favored the control group, that is, the population receiving radical cystectomy as a primary treatment, as shown in Figure 3.  2022), significantly contribute to robust evidence supporting the efficacy of radical cystectomy in improving overall survival in patients with MIBC [35].The study demonstrated a noteworthy increase in overall survival rates among patients undergoing RC compared to those who opted for bladder-sparing trimodal therapy, reinforcing the curative potential of surgical intervention [35].This aligns with previous evidence that highlights the curative potential of radical cystectomy.However, discrepancies across studies, notably the study by Yamamoto et al. (2023), underscore the need for careful consideration of patient selection criteria and the potential impact of confounding variables [36].This emphasizes the reduction in disease-specific mortality after radical cystectomy.This study provided compelling evidence that radical cystectomy is associated with decreased disease-specific mortality rates, reaffirming its role as a critical intervention in managing MIBC.Compelling evidence from RCTs, such as the study by Sobhani et al. (2023), supports a reduction in disease-specific mortality after radical cystectomy [37].The meta-analysis substantiates these findings, strengthening the argument for radical cystectomy as an effective intervention to improve survival outcomes in patients with MIBC.
This study underscores the significance of achieving negative surgical margins in RC, emphasizing its pivotal role in reducing the risk of disease recurrence.Studies such as the ACS NSQIP (American College of Surgeons National Surgical Quality Improvement Program) database analysis by Zakaria et al. (2014) align with this review, reporting acceptable rates of positive surgical margins post-RC [38].Meticulous examination of surgical margins is critical for optimizing the oncological efficacy of RC.Recent evidence, including the findings of the RCT by Softness et al. (2022), supports the meta-analysis in demonstrating the importance of achieving optimal lymph node yield during RC [35].The study highlighted the association between adequate lymph node dissection and improved survival outcomes, reinforcing the pivotal role of meticulous lymphadenectomy in the surgical approach [35].The meta-analysis, corroborated by studies such as Han and Ku (2023), emphasizes a trend toward reduced hospitalization duration post-RC [39].The utilization of advanced surgical techniques, including robot-assisted surgery, is associated with shorter hospital stays, highlighting the potential impact of technological advancements on improving perioperative recovery.Beyond immediate postoperative outcomes, SRMA delves into the analysis of 90-day postoperative complications.This comprehensive approach aligns with older studies, such as the analysis by Konety et al. (2006), who explored cardiac and pulmonary complications following RC [40].The study introduces a subtle perspective, acknowledging the increased frequency of certain complications post-RC, prompting a deeper examination of perioperative management practices and potential modifiable risk factors Recent studies have contributed divergent perspectives on the post-RC QoL.Notably, Tyson and Barocas (2018) highlighted substantial improvements in physical well-being, aligning with the overall trend observed in a meta-analysis [41].However, Rudolph et al. (2020) introduce variations in emotional and social domains, emphasizing the complexity of assessing QoL post-surgery [42].The impact of urinary diversion type on QoL outcomes is a crucial consideration, as evidenced by Han and Ku (2023) [39].This study emphasizes the need for tailored approaches that recognize the influence of specific interventions on patients' postoperative experiences.
Furthermore, this research underscores the significance of incorporating patient-reported outcomes into clinical decision-making.The evolving landscape of MIBC management demands a delicate balance between oncological efficacy and QoL preservation, necessitating shared decision-making and comprehensive preoperative counseling.The findings of this study highlight the key areas for future research and clinical practice.Further investigations into refining patient selection criteria, optimizing surgical techniques, and exploring advancements in perioperative care are crucial to enhancing the overall success of radical cystectomy.The potential impact of emerging technologies, such as robot-assisted surgery, on perioperative outcomes warrants further exploration.Additionally, long-term studies focusing on QoL outcomes after radical cystectomy and comparative effectiveness research with alternative treatments will contribute to more informed decision-making in the evolving landscape of muscle-invasive bladder cancer management.Overall, these future implications underscore the dynamic nature of urological oncology and encourage ongoing efforts to tailor interventions to improve patient outcomes.

Strengths
The strengths of this study lie in its comprehensive inclusion criteria, encompassing a diverse range of recent literature on radical cystectomy outcomes in muscle-invasive bladder cancer.The study demonstrates methodological rigor, adhering to robust systematic review practices and employing metaanalytic techniques to synthesize evidence from various study designs, thereby enhancing the reliability of its findings.A notable feature is the multidimensional analysis undertaken, which systematically examined survival rates, complications, and QoL outcomes.This approach provides a holistic understanding of the implications of radical cystectomy in patients with muscle-invasive bladder cancer.Moreover, the study's focus on incorporating recent evidence, limited to studies published within the last five years, ensures a contemporary perspective, capturing the latest advancements and trends in the management of muscleinvasive bladder cancer through radical cystectomy.

Limitations
Although this study investigated the right outcomes and measures for analysis and assessment, it had several limitations.First, the sample sizes used for the meta-analysis could not be standardized according to standard protocols.We used the study characteristics in consideration but did not consider the methodological characteristics of the studies.Second, very few primary studies were utilized to assess the effectiveness (outcome domain) of such a large sample size.Third, we evaluated the overall combined effect of all sample sizes, but within-group and subgroup analyses were not performed.Several studies have demonstrated that the results of the final analysis can be significantly altered when population demographics are subgrouped into effect sizes.

Conclusions
This systematic review and meta-analysis of radical cystectomy outcomes in muscle-invasive bladder cancer provides compelling evidence supporting the efficacy of the procedure in enhancing overall survival and reducing disease-specific mortality.Despite variations in the reported complications, recent studies have underscored the acceptable risk profile associated with radical cystectomy.Meticulous examination of surgical margins, lymph node yield, length of hospital stay, and 90-day postoperative complications contribute to a comprehensive understanding of the complexities of the procedure.These findings emphasize the importance of individualized treatment approaches in the management of muscle-invasive bladder cancer, considering both oncological efficacy and perioperative outcomes.Overall, radical cystectomy remains a cornerstone intervention, with ongoing advancements poised to further refine its role in contemporary urological oncology.

FIGURE 1 :
FIGURE 1: PRISMA flow chart for selected studies PRISMA: Preferred Reporting Items for Systematic Review and Meta-Analyses OS and RFS outcomes were assessed in individuals with non-metastatic MIBC and high-risk NMIBC who underwent either RARC or ORC following a median follow-up period exceeding significant for three out of five studies, specifically by Hinsveld et al. (2022), Boustani et al. (2018), and Kim et al. (2017)[17,19,26].The calculated heterogeneity for this analysis was as follows: Tau2=0.03;Chi2=6.80,df=4 (p-value=0.15);I2=41%.Analysis of the overall effect yielded Z=2.09 (p=0.04).Remarkably, the individual effects of all studies favored the control group, indicating that the population receiving radical cystectomy as the primary treatment demonstrated better outcomes.The hazard ratio with a 95% confidence interval was reported as 1.13 (0.79, 1.62) for Boustani et al. (2018), 4.18 (1.33, 13.14) for Kim et al. (2017), and 1.08 (0.91, 1.28) for Hinsenveld et al. (

FIGURE 3 :
FIGURE 3: Forest plot for progression-free survival